This application to join the Consortium on Targeting And Regeneration as part of the Human Islet Research Network (HIRN) seeks to develop cell-based strategies to target pancreatic islets and overcome two central problems in type 1 diabetes (T1D) by (1) targeting immunoregulation to islets and suppressing immune- mediated destruction, without systemic immuno-suppression, and (2) delivering factors that improve ?-cell survival, function and/or regeneration. Advances in genetic modification of T lymphocytes have revolutionized therapeutic targeting in fields like oncology. T cells can be engineered to express chimeric antigen receptors (CAR) that direct CAR T-cells to specific antigens expressed by neoplastic cells whereupon they activate and cause tumor regression and elimination. These successes have prompted exploration of CAR technology with regulatory T cells (T reg cells) in non-neoplastic disease settings, including T1D. While those studies demonstrated safety, Treg cells ? which have the ability both to immunomodulate and deliver trophic factors supporting islet cell function and survival ? did not localize to sites where they may be needed (like islets or pancreas). This proposal is based on recent discoveries by our team that mouse Treg cells can be modified to express CAR's which bind modified antibodies to direct Treg localization to islets, and promote allograft tolerance in vivo. We have identified CAR's targeting human ?-cell antigens that direct human Treg cells to human islets in vitro and in vivo. We postulate that developing these T cell-based targeting methods will produce novel clinical strategies to prevent T1D in high risk patients, to suppress autoimmunity and preserve ?-cell mass in patients with recent-onset T1D, and to deliver therapeutics to the islet for ?-cell protection, functional improvement or regeneration in established T1D. Our team will bring to CTAR and HIRN substantial experience and new tools that could benefit the HIRN mission and its members.